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US8722896B2 - Prokineticin receptor antagonists and uses thereof - Google Patents

Prokineticin receptor antagonists and uses thereof Download PDF

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US8722896B2
US8722896B2 US13/140,314 US200913140314A US8722896B2 US 8722896 B2 US8722896 B2 US 8722896B2 US 200913140314 A US200913140314 A US 200913140314A US 8722896 B2 US8722896 B2 US 8722896B2
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ylmethyl
dihydro
benzodioxepin
chloro
carboxamide
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US20120035149A1 (en
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Qun-Yong Zhou
Jia-Da Li
Qi Huang
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University of California San Diego UCSD
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D321/00—Heterocyclic compounds containing rings having two oxygen atoms as the only ring hetero atoms, not provided for by groups C07D317/00 - C07D319/00
    • C07D321/02—Seven-membered rings
    • C07D321/10—Seven-membered rings condensed with carbocyclic rings or ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/20—Hypnotics; Sedatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the field of the invention is directed to compounds and compositions that include a prokineticin antagonist and methods therefor.
  • Prokineticins are regulatory peptides that are thought to exert signaling activity via two highly conserved G protein-coupled receptors (GPCR), the prokineticin receptor 1 (PKR1) and the prokineticin receptor 2 (PKR2).
  • GPCR G protein-coupled receptors
  • PSR1 and PPR2 Mature human prokineticins (PK1 and PK2) contain 86 and 81 amino acids, respectively, and are among the largest known ligands for all GPCRs.
  • PK1 and PK2 share about 45% amino acid identity within and among several distinct species, and a sequence alignment readily suggests that numerous PKs exhibit complete conservation of the first six amino acids and the 10 cysteine residues predicted to form five pairs of disulfide bonds.
  • prokineticins were reported as regulators of smooth muscle contractility in a study that used recombinant PK1 and PK2 to stimulate the contraction of guinea pig ileum.
  • the role of PKs in gastric and colonic contractility has also been investigated, and histological studies revealed that PKR1 is also expressed on myenteric plexus neurons and colocalizes with a small subset of NOS synthetase-expressing neurons.
  • PK may regulate gastrointestinal motility directly via activating smooth muscle cells, and indirectly via modulating the activities of enteric neurons.
  • PK2 was reported to have a regulatory function in sleep regulation, circadian rhythm and stress response. It was observed that PK2 mRNA in the suprachiasmatic nucleus (SCN) displays dramatic circadian rhythmicity under light/dark and constant dark conditions and so suggests the potential regulatory function of PK2 for the circadian clock. Subsequently, multiple lines of evidence have supported the role of PK2 as a prominent output molecule for the SCN circadian clock. Furthermore, the receptor for PK2 is expressed in virtually all known primary SCN targets, indicating that these SCN targets can respond to oscillatory PK2 signal from the SCN.
  • WO2007/067511 describes various compounds that are useful in the treatment or prevention of neurological and psychiatric disorders in which prokineticin receptors are involved, and especially for modulation of circadian rhythm and treatment of sleep disorders.
  • PK2 intracerebroventricular
  • ICV intracerebroventricular
  • mice lacking the PK2 gene PK2 ⁇ / ⁇ mice
  • PK2 ⁇ / ⁇ mice displayed significantly reduced anxiety and depression-like behaviors.
  • PK2 ⁇ / ⁇ mice show impaired responses to exposure to new environments in terms of locomotor activity, arousal, body temperature and food intake.
  • prokineticins have been reported as potent modulators for angiogenesis, hematopoiesis, and neurogenesis.
  • PK1 was identified as a molecule that was capable of inducing proliferation of primary bovine adrenal-cortex-derived capillary endothelial (ACE) cells, and delivery of PK1 in ovary elicited potent angiogenesis and cyst formation, while the angiogenic effect is absent when delivered to cornea or skeletal muscles.
  • PK1 and PK2 also drastically promoted the differentiation of mouse and human bone marrow cells into the monocyte/macrophage lineage, and PK2 promoted the survival and differentiation of granulocytic lineages in cultures of the human or mouse hematopoietic stem cells.
  • PKR1 and PKR2 are expressed in the hematopoietic stem cells. Still further, PK2 has also been reported as regulator of neurogenesis for adult mammalian brain, and PK2 appears to function as a chemoattractant for SVZ-derived neuronal progenitors.
  • prokineticin-mediated signaling has been the focus for certain methods and compositions for modulation of angiogenesis (e.g., U.S. Pat. App. No. 2004/0235732), and compositions and methods to modulate angiogenesis.
  • U.S. Pat. No. 7,323,334 teaches use of prokineticin receptor antagonists in the modulation of receptor signaling.
  • the present invention is directed to various compounds, compositions, and methods of prokineticin antagonists, and particularly small molecule non-protein prokineticin antagonists. More particularly, the compounds and compositions described herein are particularly useful in the treatment and prevention of type II diabetes and diabetic conditions and symptoms of type II diabetes.
  • contemplated compounds have a structure according to Formula 1
  • R1 is an optionally substituted aryl, optionally substituted heteroaryl, or an optionally substituted aryl with a fused heterocyclic ring
  • X and Y are independently lower alkyl
  • Q is NH or NR6, wherein R6 is lower alkyl
  • Z is CH2 or CHR7, wherein R7 is lower alkyl
  • Q and Z are covalently coupled to each other to form a heterocyclic 4- to 6-membered ring in which Q is N and Z is CH
  • R2 is lower alkylene
  • R3 is H, lower alkyl, or alkaryl
  • A is N or C
  • W is H, or halogen, or W is null where A is N
  • R4 and R5 are independently alkoxy, or are covalently coupled to each other to form an optionally substituted heterocyclic 6- or 7-membered ring with at least one oxygen atom.
  • the heterocyclic ring is not a morpholine ring.
  • R1 is optionally substituted phenyl, optionally substituted indolyl, or optionally substituted indolinyl, and/or X and Y are CH2. It is also preferred that X and Y are covalently coupled to each other to form a pyrrolidine ring, a piperidine ring, a piperazine ring, a thiomorpholine ring, or a morpholine ring.
  • R3 is an optionally branched lower alky, and/or that R4, R5, W, and the phenyl ring to which R4, R5, and W are covalently coupled form an optionally halogenated benzodioxepin ring.
  • R2 is CH2, and/or W is Cl or F.
  • a pharmaceutical composition for treatment of a condition associated with a dysfunction or dysregulation of a prokineticin receptor comprising a compound according to Formula I, and a pharmaceutically acceptable carrier.
  • the compound is present in a dosage unit for oral administration in an amount effective to treat or prevent a condition associated with a dysfunction or dysregulation of a prokineticin receptor, and it is particularly preferred that the condition is diabetes mellitus.
  • the inventors also contemplate use of a compound according to Formula I in the manufacture of a medicament for diagnosis or treatment of a condition associated with a dysfunction of a prokineticin receptor.
  • the condition is diabetes mellitus, a sleep disorder, ischemic stroke, gastrointestinal mobility disorder, pain disorder, an anxiety disorder, or a mood disorder.
  • the inventors also contemplate a method of treating, or preventing type II diabetes that includes a step of administering a prokineticin antagonist at a concentration effective to treat or prevent type II diabetes.
  • a prokineticin antagonist is a compound according to Formula I
  • FIG. 1 is a graph depicting (Panel A) the in vivo effect of an exemplary contemplated compound on glucose clearance in a glucose tolerance test and (Panel B) a dose dependent effect of the compound.
  • FIG. 2 is a graph depicting the in vivo effect of the exemplary compound on glucose clearance in a glucose tolerance test in a diet-induced hyperglycemia model.
  • FIG. 3 is a graph depicting the in vivo effect of the exemplary compound on circulating glucose levels in a diet-induced hyperglycemia model.
  • FIG. 4 is a graph depicting the in vivo effect of the exemplary compound on glucose levels under fed and fasting conditions in a diet-induced hyperglycemia model.
  • FIG. 5 is a graph depicting the in vivo effect of the exemplary compound on glucose clearance in a glucose tolerance test in PK2-deficient mice (PK2 ⁇ / ⁇ ) and wild type (WT) control mice.
  • FIG. 6 is a graph depicting the in vivo effect of the exemplary compound on the sensitivity to diet-induced hyperglycemia by feeding with high fat (HF) diets in PK2-deficient mice (PK2 ⁇ / ⁇ ) and wild type (WT) control mice under fed and fasting conditions.
  • HF high fat
  • FIG. 7 is a graph depicting the in vivo effect of the exemplary compound on glucose clearance in a glucose tolerance test in PK2-deficient mice (PK2 ⁇ / ⁇ ) and wild type (WT) control mice previously maintained on a high fat diet.
  • FIG. 8 is a graph depicting the in vivo effect of PK2 administration on glucose clearance in a glucose tolerance test in PK2-deficient mice (PK2 ⁇ / ⁇ ) and wild type (WT) control mice.
  • FIG. 9 is a collection of photomicrographs of pancreas sections immuno-stained with antibodies against insulin, PKR1, and PKR2 from fasted mice, mice fed with high fat diet, and mice fed with chow diet.
  • FIG. 10 is a graph depicting the in vivo effect of PK2 administration on insulin secretion in PK2-deficient mice (PK2 ⁇ / ⁇ ) and wild type (WT) control mice.
  • FIG. 11 is a graph depicting the in vivo effect of PK2 administration on insulin secretion in PK2-deficient mice.
  • FIG. 12 is a graph depicting various in vitro effects of PK2 and contemplated compounds on insulin secretion (Panels A and B) and cAMP levels (Panels C and D) in MIN6 cells.
  • prokineticin receptors and/or ligands can be used to treat, prevent, and/or manage type II diabetes, pre-diabetes, diabetic conditions, and/or symptoms of diabetes.
  • contemplated methods and compositions are drawn to pharmacological intervention that targets prokineticin ligand/receptor interactions (e.g., via a small molecule inhibitor and/or antagonist, antibodies against prokineticin receptors, soluble proteins/receptors of prokineticin ligand binding, and/or antibodies against prokineticin ligands, etc.), either in a single agent therapy or as a component in a combination therapy with other (preferably commercially available) treatment agents against type II diabetes.
  • contemplated compounds and compositions may indeed be used for all conditions and/or disorders that are associated with a dysregulation and/or dysfunction of the prokineticin receptor (unless specified otherwise, the term prokineticin receptor refers to PKR1 and PKR2).
  • suitable conditions and disorders include type II diabetes, sleep disorders, pain disorders, gastrointestinal mobility disorder, an anxiety disorder, or a mood disorder, and/or ischemic stroke.
  • contemplated compounds and compositions may also be used for diagnosis of conditions and/or disorders that are associated with a dysregulation and/or dysfunction of the prokineticin receptor, and it is especially contemplated that in such use the compounds will have a label that is radiologically detectable (e.g., alpha- or beta-particle emitter, NMR-detectable label, or PET or SPECT-detectable label).
  • a label that is radiologically detectable e.g., alpha- or beta-particle emitter, NMR-detectable label, or PET or SPECT-detectable label.
  • the present inventive subject matter is directed to various compounds that modulate (e.g., inhibit or reduce) the prokineticin receptor-ligand interaction, and/or that directly or indirectly affect the receptor or ligand and so interfere with signal transduction.
  • exemplary compounds will therefore include amino acid derivatives, and especially the compounds discussed herein, which act as antagonists of prokineticin receptors. Consequently, the inventors also contemplate pharmaceutical compositions comprising these compounds, and the use of these compounds and compositions in the prevention or treatment of such diseases in which prokineticin receptors are involved.
  • prokineticin inhibitors are contemplated that can generally be characterized as amino acid derivatives, where the amino acid may be an alpha-, beta-, delta-, gamma- (or even higher) amino acid and in which the amino acid may be linear or cyclic. Most typically, the amino acid will have a ‘left-hand’ modification and a ‘right-hand’ modification, and exemplary compounds are described as follows:
  • contemplated compounds have a structure according to Formula A
  • A is an amino alkylene group, with or without substituents on the amino group.
  • A is an amino alkylene group, with or without substituents on the amino group.
  • A is an amino alkylene group, with or without substituents on the amino group.
  • R1, R2, and R2′ are independently hydrogen, aryl, substituted aryl, heteroaryl, substituted heteroaryl, naphthyl, substituted naphthyl, fused bicyclic heteroaryl, or substituted fused bicyclic heteroaryl, and where D1, D1′, D2, D2′, D3, and D4 are independently a covalent bond or a C 1-8 alkylene, optionally substituted with one or more substituents.
  • substituted refers to a replacement of an atom or chemical group (e.g., H, NH2, or OH) with a functional group
  • functional groups include nucleophilic groups (e.g., —NH2, —OH, SH, —NC, etc.), electrophilic groups (e.g., C(O)OR, C(X) OH, etc.), polar groups (e.g., —OH), non-polar groups (e.g., aryl, alkyl, alkenyl, alkynyl, etc.), ionic groups (e.g., NH3+), and halogens (e.g., —F, —Cl), and all chemically reasonable combinations thereof.
  • nucleophilic groups e.g., —NH2, —OH, SH, —NC, etc.
  • electrophilic groups e.g., C(O)OR, C(X) OH, etc.
  • polar groups e.g., —OH
  • the term “functional group” as used herein refers to a nucleophilic group (e.g., —NH2, —OH, SH, —NC, —CN etc.), an electrophilic group (e.g., C(O)OR, C(X)OH, C(Halogen)OR, etc.), a polar group (e.g., —OH), a non-polar group (e.g., aryl, alkyl, alkenyl, alkynyl, etc.), an ionic group (e.g., NH3+), and a halogen.
  • a nucleophilic group e.g., —NH2, —OH, SH, —NC, —CN etc.
  • an electrophilic group e.g., C(O)OR, C(X)OH, C(Halogen)OR, etc.
  • a polar group e.g., —OH
  • a non-polar group e.g., aryl
  • E is preferably a nitrogen containing non-aromatic optionally substituted heterocyclic ring, with the basic nitrogen placed at ⁇ , ⁇ , or ⁇ position to the carbonyl group, and with the cyclic ring sized 3-7 members (unsubstituted or substituted).
  • suitable heterocyclic rings include pyrrolidine, piperidine, morpholine, thiomorpholine, piperazine, hydropyrimidine, hydropyridazine, hydrooxazine, oxazolidine, thiozolidine, imadazolidine, pyrozolidine, azetidine, azepine, diazepine, and rings having the following structures:
  • G is preferably a non-aromatic carbocyclic or non-aromatic heterocyclic ring, and most preferably a three to seven membered ring.
  • D is a covent bond or an optionally substituted C 1-8 alkylene, and Z is preferably O, S, NRz (with Rz being hydrogen, or lower alkyl (C1-C6)).
  • L is preferably hydrogen, C1-12 alkyl, which is linear or branched, unsubstituted or substituted with one or more substituents selected from alkoxyl (C1-6), halogen, alkylsulfide (C1-6), alkylsulfoxide (C1-6), alkenyl, alkynyl, cyano, nitro, cyclic alkyl, cyclic alkenyl, cyclic alkynyl, phenyl, substituted phenyl, heteroaromatics (substituents may also be J as defined below).
  • substituents selected from alkoxyl (C1-6), halogen, alkylsulfide (C1-6), alkylsulfoxide (C1-6), alkenyl, alkynyl, cyano, nitro, cyclic alkyl, cyclic alkenyl, cyclic alkynyl, phenyl, substituted phenyl, heteroaromatics (substituents
  • L may further be C3-7 cycloalkyl, which is unsubstituted or substituted with one or more substituents selected from alkoxyl (C1-6), halogen, alkylsulfide (C1-6), alkylsulfoxide (C1-6), alkenyl, alkynyl, cyano, nitro, cyclic alkyl, cyclic alkenyl, cyclic alkynyl, phenyl, substituted phenyl, heteroaromatics, substituted or unsubstituted (substituents may also be J as defined below).
  • J is preferably hydrogen, or any of the following structures:
  • Rc and Rd are independently hydrogen, halogen, alkyl (C1-6), cyano, hydroxy, alkoxy (C1-6), hydrosulfide, alkylsulfide(C1-6), nitro, amino, alkylamino (C1-6), substituted alkyl; where Het is a 5 or 6 membered heteroaryl (e.g., thiophene, thiazole, oxazole, pyridine, pyridazine, pyrimidine, pyrazine, 1,2,3-triazine, etc.), and where D4 is a covalent bond or C 1-8 alkylene.
  • heteroaryl e.g., thiophene, thiazole, oxazole, pyridine, pyridazine, pyrimidine, pyrazine, 1,2,3-triazine, etc.
  • Still further contemplated compounds will have a structure according to Formula B:
  • M1, M2, and M2′ are independently a covalent bond, a phenyl, a heteroaryl (e.g., pyridine, thiophene, furane, pyrimidine, pyrazine, or pyridazine), a naphthyl, a bicyclic heteroaryl (e.g., indole, benzofurane, benzophiophene, benzimidazole, quinoline, isoquinoline, quinazoline, indoline, dihydrobenzofurane, or benzimidazoline).
  • a heteroaryl e.g., pyridine, thiophene, furane, pyrimidine, pyrazine, or pyridazine
  • a naphthyl e.g., a bicyclic heteroaryl (e.g., indole, benzofurane, benzophiophene, benzimidazole, quinoline
  • X1, X2, and X2′ are independently hydrogen, halogen, hydroxyl, amino, alkylamino (C 1-6 , linear, branched, or cyclic (C 3-6 )), nitro, cyano, azide, optionally substituted C 1-8 alkyl (e.g., substituted with hydroxyl, nitro, hydrosulfide, amino, etc.), alkylamino (C 1-6 ), alkoxyl (C 1-6 ), halogen, cyano, alkylsulfide (C 1-6 ), carboxyl, optionally substituted C 2-6 alkenyl (e.g., substituted with C 1-6 alkyl, C 3-6 cycloalkyl, phenyl, cyano), alkoxyl (C 1-8 ), optionally substituted tetrazolyl, thienyl, thiazolyl, benzothienyl, pyrazolyl, or imidazolyl.
  • C 1-8 optionally substitute
  • D1, D2, D2′, and D3 are independently a covalent bond, an optionally substituted C 1-8 alkylene, an alkenyl (C 2 -C 6 ), an alkynyl (C 2 -C 6 ), an alkoxyl (C 1 -C 6 ), an alkylsulfidyl (C 1-6 ), an alkylsulfoxidyl (C 1-6 ), or an azidyl, and where the remaining substituents are as defined above.
  • Still further contemplated compounds will have a structure according to Formula C:
  • D4 is selected from a covalent bond, an optionally substituted C 1-8 alkylene, and where E is preferably a nitrogen containing 3-7 membered non-aromatic heterocyclic ring, with the basic nitrogen placed at ⁇ , ⁇ , or ⁇ position to the carbonyl group (e.g., pyrrolidine, piperidine, morpholine, thiomorpholine, piperazine, hydropyrimidine, hydropyridazine, hydroxazine, oxazolidine, thiozolidine, isoxazolidine, isothiozolidine, oxazoline, isoxazoline, isothioxazolin, imadazolidine, pyrozolidine, azeridine, azetidine, azepine, diazepine, etc.).
  • E therefore also includes the structures below:
  • G is a three to seven membered non-aromatic carbocyclic or non-aromatic heterocyclic ring, and preferably has a structure as shown below:
  • D7 is a covalent bond or an optionally substituted lower alkylene (C1-C6), and where HET is a 3-7 membered non-aromatic cyclic moiety which may contain one or more heteroatoms (e.g., oxygen; nitrogen, and sulfur).
  • heteroatoms e.g., oxygen; nitrogen, and sulfur
  • M1 and M2 are independently a covalent bond
  • M2′ is phenyl
  • X1 and X2 are hydrogen
  • both n1 and n2 are 1 and where the remaining substituents are as defined above.
  • D1, M1 are direct link, X1 is hydrogen, M2 is phenyl, and where the remaining substituents are as defined above; and those wherein D1, M1 are direct link, X1 is hydrogen, M2 is pyridyl, and where the remaining substituents are as defined above; and those wherein D1, M1 are direct link, X1 is hydrogen, M2 is indolyl, and where the remaining substituents are as defined above; and those wherein D1, M1 are direct link, X1 is hydrogen, M2 is benzimidazolyl, and where the remaining substituents are as defined above; and those wherein D1, M1 are direct link, X1 is hydrogen, M2 is benzofuranyl and where the remaining substituents are as defined above; and those wherein M2 is direct link, X2 is hydrogen, M1 is phenyl, and where the remaining substituents are as defined above; and those wherein M2 is direct link, X2 is hydrogen, M1 is pyridyl
  • D1, D2, M1, M2 are all direct links, X1, and X2 are hydrogen, M2′ is phenyl, and where the remaining substituents are as defined above; and those wherein D1, D2, M1, M2 are all direct links, X1 and X2 are hydrogen, M2′ is pyridyl, and where the remaining substituents are as defined above; and those wherein D1, D2, M1, M2 are all direct links, X1 and X2 are hydrogen, M2′ is indole, and where the remaining substituents are as defined above; and those wherein D1, D2, M1, M2 are all direct links, X1 and X2 are hydrogen, M2′ is benzimidazolyl, and where the remaining substituents are as defined above; and those wherein D1, D2, M1, M2 are all direct links, X1 and X2 are hydrogen, M2′ is benzofuranyl, and where the remaining substituents are as defined above; and those wherein D2, D2′, M2
  • contemplated compounds will have a structure according to Formula 1
  • R1 is an optionally substituted aryl, optionally substituted heteroaryl, or an optionally substituted aryl with a fused heterocyclic ring
  • X and Y are independently lower alkyl
  • Q is NH or NR6, wherein R6 is lower alkyl
  • Z is CH2 or CHR7, wherein R7 is lower alkyl
  • Q and Z are covalently coupled to each other to form a heterocyclic 4- to 6-membered ring in which Q is N and Z is CH
  • R2 is lower alkylene
  • R3 is H, lower alkyl, or alkaryl
  • A is N or C
  • W is H, or halogen, or W is null where A is N
  • R4 and R5 are independently alkoxy, or are covalently coupled to each other to form an optionally substituted heterocyclic 6- or 7-membered ring with at least one oxygen atom.
  • R1 is optionally substituted phenyl, optionally substituted indolyl, or optionally substituted indolinyl. It is also particularly preferred that X and Y are CH2, or that X and Y are covalently coupled to each other to form a pyrrolidine ring, a piperidine ring, a piperazine ring, a thiomorpholine ring, or a morpholine ring. Additionally, or alternatively R3 is an optionally branched lower alkyl, and/or R4, R5, W, and the phenyl ring to which R4, R5, and W are covalently coupled form an optionally halogenated benzodioxepin ring. Most typically, but not necessarily, R2 is CH2, and/or W is Cl or F. Still further particularly preferred compounds are presented in the table preceding the claims.
  • Certain compounds contemplated herein may comprise one or more asymmetric centers, and therefore exist in different enantiomeric forms. It should be recognized that all enantiomeric forms of contemplated compounds are specifically contemplated herein. Similarly, where contemplated compounds exhibit optical activity and/or have stereoisomers, all isomeric forms are contemplated herein. Furthermore, where double bonds distinguish a Z-form from an E-form (or cis- from trans-), both isomers are contemplated.
  • the compounds according to the inventive subject matter may also be isotopically-labeled.
  • suitable isotopes 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 18 F, or 36 Cl may be useful in drug and/or substrate tissue distribution assays.
  • substitution with non-radioactive isotopes e.g., 2 H or 13 C
  • Contemplated compounds may be prepared as pharmaceutically acceptable salt(s), which especially include salts of acidic or basic groups which may be present in the contemplated compounds.
  • contemplated compounds that are basic in nature may form a wide variety of salts with various inorganic and organic acids.
  • Suitable acids will provide pharmacologically acceptable anions, including chloride, bromide, iodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, acid citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate[1,1′-methylene-bis-(2-hydroxy-3-naphthoate)]anions.
  • compounds that are acidic in nature may form base salts with various pharmacologically acceptable cations, and especially suitable cations include alkali metal or alkaline earth metal
  • compounds according to the inventive subject matter may also be prepared as prodrugs, and all known manners and types of prodrugs are considered suitable for use herein, so long as such prodrug will increase the concentration of the drug (or metabolite of the prodrug) at a target organ or target cell.
  • prodrugs particularly include those in which contemplated compounds forms an ester, amide, or disulfide bond with another cleavable moiety.
  • Such moieties may assist in organ or cell-specific delivery of the drug.
  • a carboxyl group can be derivatized to form an amide or alkyl ester, which may include an ether, amine-, and/or carboxylic acid group.
  • Free hydroxy groups may be derivatized using hemisuccinates, phosphate esters, dimethylaminoacetates, and phosphoryloxymethyloxycarbonyls, as outlined in D. Fleisher, R. Bong, B. H. Stewart, Advanced Drug Delivery 40 Reviews (1996) 19, 115.
  • Carbamate prodrugs of hydroxy and amino groups are also included, as are carbonate prodrugs and sulfate esters of hydroxy groups.
  • contemplated compounds may be metabolized in a cell or extracellular compartment, and that such metabolites may exhibit the same or different pharmacological effect.
  • contemplated compounds may be phosphorylated and thus be more active than the parent compound.
  • reduction or glycosylation may affect bioavailability of contemplated compounds. Consequently, contemplated compounds will not only include those as described above, but also include metabolites thereof.
  • contemplated compounds may be formulated for treatment of various diseases associated with dysregulation and/or dysfunction of PK receptors and/or overexpression of such receptors. Therefore, and among other contemplated uses, the inventors especially contemplate that pharmaceutical compositions comprising contemplated compounds may be effective for the treatment or prevention of type II diabetes, wherein contemplated pharmaceutical compositions comprise a therapeutically effective amount of contemplated compounds (or pharmaceutically acceptable salt, hydrate, or prodrug thereof), and a pharmaceutically acceptable carrier.
  • contemplated compositions are formulated for treatment of type II diabetes.
  • type II diabetes and/or symptoms thereof can be prevented or treated by administration of a prokineticin antagonist (wherein suitable antagonists include those than bind to the PK receptor, disrupt and/or prevent PK receptor-ligand interaction, or even bind to a PK receptor ligand).
  • a prokineticin antagonist wherein suitable antagonists include those than bind to the PK receptor, disrupt and/or prevent PK receptor-ligand interaction, or even bind to a PK receptor ligand.
  • contemplated compositions may be formulated for treatment of non-diabetic conditions and include those associated with smooth muscle contraction, pain perception, inflammation, sleep disorders, stress, and neurologic/psychiatric disorders.
  • contemplated compounds are included in a composition that is formulated with one or more non-toxic pharmaceutically acceptable carriers.
  • Suitable pharmaceutical compositions are preferably formulated for oral administration in solid or liquid form, or for parenteral injection.
  • pharmaceutical compositions according to the inventive subject matter may be administered to humans and other animals using various routes, including orally, rectally, parenterally, intraperitoneally, vaginally, or topically.
  • suitable pharmaceutical compositions for injection preferably comprise pharmaceutically acceptable sterile aqueous or nonaqueous solutions, dispersions, emulsions, or suspensions, as well as sterile powders for reconstitution into sterile injectable solutions or dispersions prior to use.
  • suitable aqueous and nonaqueous carriers, diluents, solvents, or vehicles include water, ethanol, polyols (e.g., glycerol, propylene glycol, polyethylene glycol, etc.), and suitable mixtures thereof, oils, and injectable organic esters (e.g., ethyl oleate).
  • Contemplated compositions may also contain various inactive ingredients, including preservatives, wetting agents, emulsifying agents, and/or dispersing agents. Sterility may be ensured by inclusion of antibacterial and/or antifungal agents (e.g., paraben, phenol sorbic acid, chlorobutanol, etc.). Where appropriate, osmotically active agents may be included (e.g., sugars, sodium chloride, etc.).
  • antibacterial and/or antifungal agents e.g., paraben, phenol sorbic acid, chlorobutanol, etc.
  • osmotically active agents may be included (e.g., sugars, sodium chloride, etc.).
  • contemplated compositions may be formulated into solid dosage forms for oral administration, and may therefore be capsules, tablets, pills, powders, and granules.
  • contemplated compound are mixed with at least one of a pharmaceutically acceptable excipient or carrier (e.g., sodium citrate or dicalcium phosphate), a filler or extender (e.g., starch, lactose, sucrose, glucose, mannitol, or silicic acid), a binder (e.g., carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, etc.), a humectant (e.g., glycerol), a disintegrating agent (e.g., agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, or sodium carbonate), a solution retarding agent (e.g., paraffin), an absorption accelerator (e.g., quatern
  • Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art.
  • Contemplated compositions may further be formulated to release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions which can be used include polymeric substances and waxes.
  • Contemplated compounds may also be in micro-encapsulated form, if appropriate, with one or more of the above-mentioned excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs.
  • liquid dosage forms may contain inert diluents commonly used in the art (e.g., water, or other solvent, solubilizing agents), emulsifiers (e.g., ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethyl formamide), oils (and in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • the oral compositions may also include adjuvants such as wetting agents, emuls
  • compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at room temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at room temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • Compounds according to the inventive subject matter can also be administered in form of liposomes, which may be unilamellar, oligolamellar, or polylamellar. Contemplated compositions in liposome form may further contain stabilizers, preservatives, excipients, etc.
  • Preferred lipids for liposome formation include phospholipids and the phosphatidyl cholines (lecithins), both natural and synthetic. Methods to form liposomes are known in the art. See, for example, Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, New York, N.Y. (1976), p. 33 et seq.
  • contemplated compounds in pharmaceutical compositions may be varied so as to obtain an amount of contemplated compound(s) that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration.
  • the selected dosage level will depend upon various factors, including the activity of the particular compound, the route of administration, the severity of the condition being treated, and the condition and prior medical history of the patient being treated.
  • dosage levels of about 0.01 mg to about 500 mg, more preferably of about 0.5 mg to about 50 mg of contemplated compound per kilogram of body weight per day are administered orally to a mammalian patient.
  • the effective daily dose may be divided into multiple doses for purposes of administration, e.g., two to four separate doses per day.
  • contemplated pharmaceutical compositions may also include additional pharmaceutically active compounds, and especially contemplated additional pharmaceutically active compounds include anti-diabetic agents, which may act on insulin production, insulin release, insulin sensitivity, and glucose uptake into a cell. Still other suitable active agents include anti-inflammatory agents, drugs that stimulate or modify metabolism, neurologically active drugs, and/or analgesic drugs.
  • additional pharmaceutically active compounds may be included in the same pharmaceutical composition, or may be administered separately, and a person of ordinary skill in the art will readily determine schedule and route of suitable co-administration of the additional pharmaceutically active compounds.
  • contemplated compositions may also include metabolites and/or prodrug forms of contemplated compounds, and that all compounds may be present in racemic mixture or sterochemically pure (or partially purified) form.
  • Synthesis of the compound of Formula A can be accomplished through a variety of methods, and in accord with its structural subcategory.
  • structure I can be broken down into two main precursors, an amino acid II and an amine III, which could be a primary or secondary amine, as depicted in Scheme 1.
  • Amine III is usually prepared from alkylation of an alkyl amine L-NH2 (IIIa) with an arylcarboaldehyde (IIIb) under reductive amination conditions, such as sodium triacetoxy borohydride in the presence of acetic acid as reagents and in an appropriate solvent such as dichloroethane (Tetrahedron Letters, 1990, 5595), as in Scheme 2.
  • Amino acid II is subcategorized into cyclic amino acid as defined in Formula A which contains E or G, or linear amino acid, all of which bearing an arylalkyl substituent on the amino group or a neighboring atom.
  • the arylalkyl group is substituted on the amino group of the amino acid, usually the connection is made via a reductive amination step with a desired aldehyde under the common reagents such as sodium triacetoxy borohydride in the presence of acetic acid and in an appropriate solvent such as dichloroethane (Tetrahedron Letters, 1990, 5595), as shown in Scheme 3.
  • the final molecule Ia can then be coupled together with amino acid II and amine III under the usual amide coupling conditions, using EDAC/HOBt or HOAt as coupling reagents, with/without DMAP, in a desired solvent such as DCM, or THF, or DMF.
  • a desired solvent such as DCM, or THF, or DMF.
  • Compound III may be coupled with an appropriately protected (Boc, Fmoc, or CBZ, etc) amino acid to form amide IX. Then releasing the amino group via a deprotection procedure was followed by a second reductive amination of the amino group with a desired aldehyde to give Compound Ia, as presented in Scheme 5.
  • a substituted amino acid precursor such as IIa and IIc can also be prepared via reductive amination between a ketoacid (or ester) and a properly substituted amine, as depicted in Scheme 6.
  • alkylamine is alkylated with arylcarboaldehyde 1 under reductive amination conditions.
  • the resulting secondary amine was then coupled with a Boc protected ⁇ -proline 4 to give amide 5, the Boc group is then removed via treatment of TFA to give 6.
  • Second reductive amination with the desired arylcarboaldehyde 7 afforded the final desired compound 8, as in Scheme 7.
  • halogenated secondary amine 13 was prepared from hydrolysis of starting monoether 9, followed by dioxepine ring formation to give the benzodioxepine-carboaldehyde 12, which leads to the desired amine 13.
  • contemplated compounds may be prepared from various precursors following numerous routes (either individually, serially, or in parallel fashion, or even using combinatorial synthetic strategies). The following is therefore only provided as exemplary guidance for starting materials, conditions, and synthesis of selected compounds.
  • Step 1 3-chloro-4,5-dihydroxy benzaldehyde: A solution of 19.1 g 3-chloro-4-hydroxy-5-methoxy benzaldehyde in dichloromethane (1600 ml) was cooled in ice water bath. Boron tribromide (53.8 g) in dichloromethane (80 ml) were added and the mixture was stirred for two hours at ambient temperature and then was concentrated. The residue was cooled again with ice water bath and precipitated with ice-cold aqueous hydrochloric acid (1N, 500 ml). Solid residue was received upon filtration, then washed with ice water (500 ml) and dried in the air to obtain 19.3 g crude product of 3-chloro-4,5-dihydroxy benzaldehyde, which was used for the following step.
  • Step 3 N-(9-chloro-3,4-dihydro-2H-1,5-benzodioxepin-7-ylmethyl)-2-methylpropan-1-amine: To an ice cold mixture of 9-chloro-3,4-dihydro-2H-1,5-benzodioxepine-7-carbaldehyde (2.07 g) and of isobutylamine (7.5 ml 8 eq.) were combined in 1,2-dichloroethane (75 ml) and cooled in ice water bath. Acetic acid (5.68 ml) was then added and followed by sodium triacetoxyborohydride (2.75 g, 1.4 eq.). The mixture was allowed to stir at room temperature overnight.
  • Step 4 (+)-(2S)-2-(Methylpropan-2-yl)oxycarbonylamino-N-(9-chloro-3,4-dihydro-2H-1,5-benzodioxepin-7-ylmethyl)-N-isobutylpropanamide: A mixture of N-(9-chloro-3,4-dihydro-2H-1,5-benzodioxepin-7-ylmethyl)-2-methylpropan-1-amine (100 mg), Boc-L-alanine (70 mg), EDAC (100 mg), and DMAP (60 mg) in DCM (8 ml) was stirred overnight. The reaction mixture was partitioned between EtOAc and water (8 ml each ⁇ 3).
  • Step 5 (+)-(2S)-2-Amino-N-(9-chloro-3,4-dihydro-2H-1,5-benzodioxepin-7-ylmethyl)-N-isobutylpropanamide:
  • the above product was dissolved in DCM (2.5 ml) and TFA (2.5 ml) was added. After stirring for one hour at room temperature, the reaction mixture was concentrated under reduced pressure. The residue was partitioned between dichloromethane (5 ml), and aqueous Na2CO3 (Sat., 10 ml). The aqueous layer was extracted with 5 ml of dichloromethane twice.
  • Step 1 ( ⁇ )-2-Methyl-3-[(2-methylpropan-2-yl)oxycarbonylamino]propanoic acid: A mixture of ( ⁇ )-2-Methyl-3-aminopropanoic acid (700 mg), di-tert-butyl pyrocarbonate (2.219 g), and triethylamine (1.375 g) in DCM (200 ml) was stirred over night in room temperature. The solvent was evaporated in vac and the solid residue was used for the next step.
  • Step 2 ( ⁇ )-2-Methyl-3-(methylpropan-2-yl)oxycarbonylamino-N-(9-chloro-3,4-dihydro-2H-1,5-benzodioxepin-7-ylmethyl)-N-isobutylpropanamide: The mixture of N-(9-chloro-3,4-dihydro-2H-1,5-benzodioxepin-7-ylmethyl)-2-methylpropan-1-amine (600 mg), ( ⁇ )-2-Methyl-3-[(2-methylpropan-2-yl)oxycarbonylamino]propanoic acid (200 mg), 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (475 mg) and of dimethyl aminopyridine (284 mg) in DCM (30 ml) was stirred overnight.
  • reaction mixture was partitioned between ethyl acetate and water (30 mL each). The aqueous layer was extracted with EtOAc (30 mL ⁇ 2). The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • Step 3 ( ⁇ )-2-Methyl-3-amino-N-(9-chloro-3,4-dihydro-2H-1,5-benzodioxepin-7-ylmethyl)-N-isobutylpropanamide: The above ( ⁇ )-2-Methyl-3-(methylpropan-2-yl)oxycarbonylamino-N-(9-chloro-3,4-dihydro-2H-1,5-benzodioxepin-7-ylmethyl)-N-isobutylpropanamide was dissolved in dichloromethane (3 ml) and treated with trifluoroacetic acid (3 ml). After stirring for two hours at room temperature, the reaction mixture was concentrated under reduced pressure.
  • Step 4 ( ⁇ )-2-Methyl-3-(benzylamino)-N-(9-chloro-3,4-dihydro-2H-1,5-benzodioxepin-7-ylmethyl)-N-isobutylpropanamide: The mixture of ( ⁇ )-2-Methyl-3-amino-N-(9-chloro-3,4-dihydro-2H-1,5-benzodioxepin-7-ylmethyl)-N-isobutylpropanamide (85 mg), of benzaladehyde (20 mg), of glacial acetic acid (90 ⁇ l), and sodium triacetoxyborohydride (51 mg) in dichloromethane (5 ml) was stirred overnight.
  • Step 1 ( ⁇ )-2-Methyl-3-(benzyl(methyl)amino)-N-(9-chloro-3,4-dihydro-2H-1,5-benzodioxepin-7-ylmethyl)-N-isobutylpropanamide: A mixture of ( ⁇ )-2-Methyl-3-(benzylamino)-N-(9-chloro-3,4-dihydro-2H-1,5-benzodioxepin-7-ylmethyl)-N-isobutylpropanamide (26 mg), paraformaldehye (16 mg), glacial acetic acid (90 ⁇ l) and sodium triacetoxyborohydride (26 mg) was dissolved in tetrahydrofuran (5 ml), and stirred overnight.
  • Step 1 ( ⁇ )-2-Methyl-3-((2-nitro)benzylamino)-N-(9-chloro-3,4-dihydro-2H-1,5-benzodioxepin-7-ylmethyl)-N-isobutylpropanamide: A mixture of ( ⁇ )-2-Methyl-3-amino-N-(9-chloro-3,4-dihydro-2H-1,5-benzodioxepin-7-ylmethyl)-N-isobutylpropanamide (94 mg), 3-nitrobenzaldehyde (40 mg), glacial acetic acid (90 ⁇ l), and sodium triacetoxyborohydride (78 mg) in dichloromethane (5 ml) was stirred overnight.
  • reaction mixture was partitioned between aq. K2CO3 (1N, 10 mL) and ethyl acetate (5 ml). The aqueous was washed with EtOAc (5 mL ⁇ 2). Organic layers were combined, washed with brine, dried with anhydrous sodium sulfate, and concentrated.
  • Step 2 ( ⁇ )-2-Methyl-3-((2-amino)benzylamino)-N-(9-chloro-3,4-dihydro-2H-1,5-benzodioxepin-7-ylmethyl)-N-isobutylpropanamide: A mixture of ( ⁇ )-2-Methyl-3-((2-nitro)benzylamino)-N-(9-chloro-3,4-dihydro-2H-1,5-benzodioxepin-7-ylmethyl)-N-isobutylpropanamide (80 mg), ammonium chloride (53 mg), and zinc powder (106 mg) in 6 ml of EtOH—H2O (9-10) was stirred overnight, and then filtered through a layer of zeolite.
  • the filtercake was rinsed with methanol (5 ml ⁇ 3), and the combined filtrate was concentrated under reduced pressure. The residue was then partitioned between of dichloromethane and saturated aq. sodium bicarbonate (6 ml each). The aqueous layer was then extracted with dichloromethane (6 ml).
  • Step 1 1-(3,4-dihydro-2H-1,5-benzodioxepine-7-yl)-4-methyl-1-penten-3-one:
  • MeOH 5 mL
  • 3,4-dihydro-2H-1,5-benzodioxepine-7-carbaldehyde 445 mg
  • 3-methyl-2-butanone 195 mg
  • the reaction was partitioned between 10 ml water and 40 ml ethyl acetate. The organic layer was then sequentially washed with aq.
  • Step 3 ( ⁇ )-1-(3,4-dihydro-2H-1,5-benzodioxepine-7-yl)-4-methylpentan-3-ylamine:
  • the above product was dissolved in ethanol (20 ml) and suspended with Pd—C (10%, 60 mg).
  • the hydrogenation was carried in a hydrogen balloon for 3 hrs at room temperature.
  • the reaction mixture was then filtered through a layer of zeolite and the filtercake was rinsed with 10 ml of methanol three times.
  • Step 4 ( ⁇ )-2-Methyl-3-[(2-methylpropan-2-yl)oxycarbonylamino]-N-[(3,4-dihydro-2H-1,5-benzodioxepin-7-yl)-4-methylpentan-3-yl]propanamide: 50 mg of ( ⁇ )-1-(3,4-dihydro-2H-1,5-benzodioxepine-7-yl)-4-methylpentan-3-ylamine was mixed with of ( ⁇ )-2-Methyl-3-[(2-methylpropan-2-yl)oxycarbonylamino]propanoic acid (25 mg), 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (53 mg), and DMAP (33 mg) in dichloromethane (5 ml) and stirred overnight.
  • Step 5 ( ⁇ )-2-Methyl-3-amino-N-[(3,4-dihydro-2H-1,5-benzodioxepin-7-yl)-4-methylpentan-3-yl]propanamide:
  • dichloromethane 2.5 ml
  • trifluoroacetic acid 2.5 ml
  • the reaction mixture was concentrated under reduced pressure.
  • the residual was partitioned between dichloromethane and aq. sodium carbonate (sat., 5 ml each).
  • Step 6 ( ⁇ )-2-Methyl-3-(benzylamino)-N-[(3,4-dihydro-2H-1,5-benzodioxepin-7-yl)-4-methylpentan-3-yl]propanamide: 21 mg ( ⁇ )-2-Methyl-3-amino-N-[(3,4-dihydro-2H-1,5-benzodioxepin-7-yl)-4-methylpentan-3-yl]propanamide, benzaladehyde (6.6 mg), glacial acetic acid (90 ⁇ l), and sodium triacetoxyborohydride (19 mg) were mixed in dichloromethane (5 ml) and stirred overnight. After addition of aq.
  • Step 1 N-(9-chloro-3,4-dihydro-2H-1,5-benzodioxepin-7-ylmethyl)-N-isobutyl 3-[(2-methylpropan-2-yl)oxycarbonylamino]propanamide: A mixture of N-(9-chloro-3,4-dihydro-2H-1,5-benzodioxepin-7-ylmethyl)-2-methylpropan-1-amine (140 mg), 3-[(2-methylpropan-2-yl)oxycarbonylamino]propanoic acid (Boc-beta-alanine, 98 mg), of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (163 mg), and of dimethyl aminopyridine (113 mg) in dichloromethane (10 ml) was stirred overnight.
  • 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride 16
  • Step 2 3-Amino-N-(9-chloro-3,4-dihydro-2H-1,5-benzodioxepin-7-ylmethyl)-N-isobutyl propanamide:
  • Step 3 3-Benzylamino N-(9-chloro-3,4-dihydro-2H-1,5-benzodioxepin-7-ylmethyl)-N-isobutyl-propanamide: The mixture of 3-Amino-N-(9-chloro-3,4-dihydro-2H-1,5-benzodioxepin-7-ylmethyl)-N-isobutyl-propanamide (54 mg), of benzaladehyde (17 mg), glacial acetic acid (90 ⁇ l), and of sodium triacetoxyborohydride (67 mg) in DCM (5 ml) was stirred overnight. To the reaction were added distilled water (3 ml) and then aq.
  • Step 1 40 mg of N-(9-chloro-3,4-dihydro-2H-1,5-benzodioxepin-7-ylmethyl)-2-methylpropan-1-amine was combined with 28 mg of 1-benzyl-azetidine-3-carboxylic acid in 5 ml dichloromethane. 38 mg of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and 26 mg of dimethyl aminopyridine were added. The reaction solution was stirred at room temperature overnight. 5 ml of water was added and the mixture was extracted with 5 ml ethyl acetate three times.
  • Step 1 ( ⁇ )-1-Benzyl-N-(3,4-dihydro-2H-1,5-benzodioxepin-7-ylmethyl)-N-isobutylpyrrolidine-3-carboxamide:
  • the above amine product, N-(9-chloro-3,4-dihydro-2H-1,5-benzodioxepin-7-ylmethyl)-2-methylpropan-1-amine (807 mg, 3 mmole) was combined with 1-Benzyl-pyrrolidine-3-carboxylic acid (615 mg, 3 mmole) in 50 ml dichloromethane.
  • Step 1 (3R)-1-tert-butoxycarbonyl-N-(9-chloro-3,4-dihydro-2H-1,5-benzodioxepin-7-ylmethyl)-N-isobutyl pyrrolidine-3-carboxamide: A mixture of N-(9-chloro-3,4-dihydro-2H-1,5-benzodioxepin-7-ylmethyl)-2-methylpropan-1-amine (1,594 mg), (R)-Pyrrolidine-1,3-dicarboxylic acid 1-tert-butyl ester 1,270 mg, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1,480 mg), dimethyl aminopyridine (1,030 mg) in 110 ml dichloromethane was stirred at room temperature overnight.
  • Step 2 (3R)—N-(9-chloro-3,4-dihydro-2H-1,5-benzodioxepin-7-ylmethyl)-N-isobutyl pyrrolidine-3-carboxamide:
  • dichloromethane 20 ml
  • trifluoroacetic acid 20 ml
  • the mixture was stirred for one hour at room temperature.
  • the residue was partitioned between dichloromethane (20 ml) and aq. sodium bicarbonate (sat., 40 mL).
  • the aqueous was extracted with 50 ml of dichloromethane twice.
  • Step 1 3-Oxo-cyclopentanecarboxylic acid benzyl ester: The mixture of 3-oxo-cyclopentanecarboxylic acid (750 mg), of benzyl alcohol (633 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride 1 (680 mg), and of 1-hydroxybenzotriazole (350 mg) in 50 ml tetrahydrofuran was stirred overnight. After addition of aq. Sodium bicarbonate (sat. 25 mL), the reaction mixture was extracted with of ethyl acetate (50 ml ⁇ 2). The organic layer was washed with brine, dried with anhydrous sodium sulfate and concentrated to yield 3-oxo-cyclopentanecarboxylic acid benzyl ester as oil.
  • Step 3 3-Phenylaminocyclopentanecarboxylic acid: Benzyl ester of 3-phenylaminocyclopentanecarboxylic acid (65 mg) was dissolved in tetrahydrofuran (5 mL) and aq. hydrochloride (6N, 5 mL). The mixture was stirred at room temperature overnight. The solvent was removed in vacuo to yield the hydrochloric salt of the desired product, which was used for the next reaction without further purification.
  • Step 4 ( ⁇ )-N-(3,4-dihydro-2H-1,5-benzodioxepin-7-ylmethyl)-N-isobutyl-3-(phenylamino)cyclopentanecarboxamide: The mixture of N-(9-chloro-3,4-dihydro-2H-1,5-benzodioxepin-7-ylmethyl)-2-methylpropan-1-amine (17 mg), 3-phenylaminocyclopentanecarboxylic acid (15 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (20 mg), and N,N-dimethyl-4-aminopyridine (12 mg) in 5 ml dichloromethane was stirred at room temperature overnight.
  • Step 1 ( ⁇ )-4-tert-butoxycarbonyl-N-(9-chloro-3,4-dihydro-2H-1,5-benzodioxepin-7-ylmethyl)-N-isobutyl thiomorpholine-2-carboxamide: The mixture of N-(9-chloro-3,4-dihydro-2H-1,5-benzodioxepin-7-ylmethyl)-2-methylpropan-1-amine (150 mg), thiomorpholine-2,4-dicarboxylic acid 4-tert-butyl ester (137 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (138 mg), and dimethyl aminopyridine (92 mg) in dichloromethane (15 ml) was stirred at room temperature overnight.
  • Step 2 ( ⁇ )-N-(9-chloro-3,4-dihydro-2H-1,5-benzodioxepin-7-ylmethyl)-N-isobutyl thiomorpholine-2-carboxamide:
  • Step 3 ( ⁇ )-4-Benzyl-N-(9-chloro-3,4-dihydro-2H-1,5-benzodioxepin-7-ylmethyl)-N-isobutylthiomorpholine-2-carboxamide: The mixture of ( ⁇ )-N-(9-chloro-3,4-dihydro-2H-1,5-benzodioxepin-7-ylmethyl)-N-isobutyl thiomorpholine-2-carboxamide (40 mg), benzaladehyde (32 mg), glacial acetic acid (0.072 ml), and sodium triacetoxyborohydride (36 mg) in 5 ml dichloromethane was stirred overnight. After addition of aq.
  • Step 1 ( ⁇ )-4-Benzyl-N-(9-chloro-3,4-dihydro-2H-1,5-benzodioxepin-7-ylmethyl)-N-isobutyl piperazine-2-carboxamide: The mixture of N-(9-chloro-3,4-dihydro-2H-1,5-benzodioxepin-7-ylmethyl)-2-methylpropan-1-amine (84 mg), 4-benzyl-piperazine-1,2-dicarboxylic acid 1-tert-butyl ester (100 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (90 mg), and dimethyl aminopyridine (53 mg) in dichloromethane (8 ml) was stirred at room temperature overnight.
  • Step 2 ( ⁇ )-4-benzyl-N-(9-chloro-3,4-dihydro-2H-1,5-benzodioxepin-7-ylmethyl)-N-isobutyl piperazine-2-carboxamide:
  • dichloromethane 2.5 ml
  • trifluoroacetic acid 2.5 ml
  • the mixture was stirred for one hour at room temperature.
  • dichloromethane 5 ml
  • the aqueous was extracted with dichloromethane (5 ml ⁇ 2).
  • aequorin-based luminescent assay for calcium mobilization was used to measure mobilization of intracellular Ca 2+ (Bullock et al., Mol Pharmacol 65, 582-588, 2004).
  • Chinese hamster ovary (CHO) cells stably expressing photoprotein aequorin and recombinant PKR1 or PKR2 were tested by this method. Briefly, the cells were charged in Opti-MEM (Invitrogen) containing 8 ⁇ M of coelenterazine cp at 37° C. for 2 hours.
  • Luminescence measurements were made using a Berthold luminometer.
  • FIG. 1 Panel (A) shows that 3Cl-R-PLP at 4 mg/kg of body weight improved glucose clearance significantly in GTT.
  • Panel (B) shows the dose-dependent effect of 3Cl-R-PLP on the performance in GTT at the concentrations of 0, 1, 4, 12, and 40 mg/kg of body weight.
  • High fat diet was fed to mice for 8 weeks to induced diet-induced hyperglycemia.
  • GTT test was carried out as described earlier.
  • 3Cl-R-PLP 40 mg/kg body weight significantly improved glucose clearance in GTT test in these diet-induced hyperglycemia models as can be seen from FIG. 2 .
  • Diet-induced diabetes models were created by feeding with high-fat diet for 8 weeks. These mice developed glucose intolerance and hyperglycemia. 3Cl-R-PLP was dissolved in drinking water and given to mice for two weeks. Circulating glucose levels were measured 3, 7 and 14 days after 3Cl-R-PLP treatment. 3Cl-R-PLP at concentration of 0.1 and 0.01 mg/ml effectively decreased the glucose levels as can be taken from FIG. 3 .
  • Db/db mice are commonly used as genetic models of type II diabetes. 10-week old db/db mice were treated with 3Cl-R-PLP (0.1 mg/mL in drinking water) or vehicle for 2 weeks. The figure below shows that 3Cl-R-PLP treatment significantly decreased glucose levels in db/db mice under both fed and fasting conditions as is shown in FIG. 4 .
  • PK2-Deficient Mice have Enhanced Glucose Clearance Abilities and are Resistant to Diet-Induced Hyperglycemia
  • PK2-deficient mice PK2 ⁇ / ⁇
  • WT wild type mice
  • PK2-deficient mice and wild type control mice were then tested for their sensitivities to diet-induced hyperglycemia by feeding with high fat (HF) diets for 8 or 16 weeks.
  • HF high fat
  • PK2-deficient mice exhibited significant resistance to diet-induced hyperglycemia as is readily evident from FIG. 6 .
  • PK2-deficient mice were also carried out in PK2-deficient mice and wild type control mice that were fed for high fat diet for 8 weeks. As with feeding with regular chows, PK2-deficient mice possessed enhanced capabilities to clear glucose delivered by i.p. Typical results are shown in FIG. 7 .
  • PK2 at doses of 10 nmol/kg and 200 nmol/kg significantly reduced the rate of glucose clearance as can be seen from FIG. 8 . This is consistent with observations that PK2-deficient mice have enhanced glucose clearance abilities.
  • PK2 and/or its two cognate receptors, PKR1 and PKR2 are expressed in pancreas beta cells.
  • In situ hybridization with mouse pancreas sections indicated that PK2, along with both PKR1 and PKR2 are expressed in pancreas islets (circled) that were also insulin immuno-positive as is shown in the photomicrographs of FIG. 9 .
  • This expression pattern suggested that PK2 signaling may directly regulate the insulin secretion from pancreas beta cells. Delivery of glucose by i.p. significantly increased circulating insulin levels (30 min).
  • PK2 insulin-induced insulin secretion was inhibited by PK2.
  • FIG. 10 administration of PK2 significantly inhibited glucose-induced elevation of insulin in circulation. Consistent with the inhibitory effect of PK2 on insulin secretion, PK2-deficient mice have increased circulating insulin level. It is likely that at least some of glucose-lowering effects of PK2 antagonists were due to their abilities to increase insulin secretion as depicted in FIG. 11 .
  • PK2 Signaling Inhibits Insulin Secretion Via Modulating Camp Level in the ⁇ -Cell Like MIN6 Cells
  • PK2 receptor antagonist 4Ind-3Cl-R-BMA PKRA
  • 4Ind-3Cl-R-BMA alone enhanced the high glucose-stimulated insulin secretion but not basal insulin secretion in MIN6 cells under low glucose, implying that the endogenous PK2 may be released by high glucose from ⁇ -cells and then functioned locally as a paracrine or autocrine factor.
  • PK2 receptors have been reported coupling to Gi or Gq proteins, the inventors examined the possible signaling transduction of PK2 receptor in MIN6 cells. Whereas PK2 didn't elicit cytosolic calcium mobilization in MIN6 cells, it significantly inhibited forskolin-induced cAMP levels in MIN6 cells (Panel C of FIG.
  • the following compounds were prepared using the above synthetic routes and protocols by varying the starting materials, reagents or conditions used.
  • the requisite reagents were either commercially available, described in the literature, or readily synthesized by one skilled in the art.
  • the potency of these compounds in antagonizing PK2-stimulated calcium mobilization were tested in Chinese hamster ovary (CHO) cells that stably express recombinant PKR1 or PKR2.

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WO2017177026A1 (fr) 2016-04-06 2017-10-12 The Regents Of The University Of California Compositions et procédés de traitement des troubles des rythmes circadien et diurne au moyen d'agonistes et d'antagonistes de prokinéticine 2
WO2018108862A1 (fr) 2016-12-12 2018-06-21 INSERM (Institut National de la Santé et de la Recherche Médicale) Antagoniste du récepteur 2 de la prokinéticine destiné à être utilisé en tant que médicament pour le traitement d'un cancer associé à un vegf

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GB201209587D0 (en) 2012-05-30 2012-07-11 Takeda Pharmaceutical Therapeutic compounds
WO2014078306A1 (fr) 2012-11-13 2014-05-22 Regeneron Pharmaceuticals, Inc. Anticorps anti-récepteur de prokinéticine (prokr) et leurs utilisations
WO2014202999A1 (fr) * 2013-06-21 2014-12-24 Takeda Cambridge Limited Dérivés de 1-sulfonyl pipéridine utilisés en tant que modulateurs des récepteurs de la prokinéticine
GB201314286D0 (en) 2013-08-08 2013-09-25 Takeda Pharmaceutical Therapeutic Compounds
GB201320905D0 (en) * 2013-11-27 2014-01-08 Takeda Pharmaceutical Therapeutic compounds
GB201420095D0 (en) 2014-11-12 2014-12-24 Takeda Pharmaceutical New use

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WO2017177026A1 (fr) 2016-04-06 2017-10-12 The Regents Of The University Of California Compositions et procédés de traitement des troubles des rythmes circadien et diurne au moyen d'agonistes et d'antagonistes de prokinéticine 2
WO2018108862A1 (fr) 2016-12-12 2018-06-21 INSERM (Institut National de la Santé et de la Recherche Médicale) Antagoniste du récepteur 2 de la prokinéticine destiné à être utilisé en tant que médicament pour le traitement d'un cancer associé à un vegf

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